Mature Th1 or Th2 cells preferentially express SOCS1 and SOCS3, respectively, suggesting possible involvement of SOCS proteins in Th1/Th2 lineage commitment. Here, we examined whether this pattern of SOCS expression is acquired early in differentiation, before commitment to either Th1 or Th2 developmental pathway. We show that SOCS genes are constitutively expressed in naive Th cells and upon activation by Ag/APC, they induce expression of SOCS1, SOCS2, and CIS genes but downregulate SOCS3. In addition to effects of TCR ligation, we found that activation of IL-4, IL-12 or IFNg signaling pathways in differentiating Th cells induces significant expression of all four SOCS members. Analysis of STAT1-null Th cells revealed that STAT1 is required for optimum induction of SOCS genes by TH1/Th2 polarizing cytokines. We also establish that IL-4 activates STAT1 and that its induction of SOCS1 and SOCS3 expression in differentiating Th cells is mediated through STAT1. We further show that IL-4 and IFNg synergize to enhance SOCS1, SOCS3 expression and inhibit IL-4-induced STAT6 phosphorylation through STAT1-dependent mechanisms. These results implicate SOCS proteins in negative feedback regulation of primary immune responses and in mediating the cross-talk between IL-4 and IFNg signaling pathways during differentiation and maturation of Th cells.